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OBJECTIVE: To evaluate the effects of early treatment with CPAP on nutritional intake and in-hospital growth rates of extremely preterm (EPT) infants. STUDY DESIGN: EPT infants (24–0/7 to 27–6/7 weeks of gestation) enrolled in the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) were included. EPT infants who died before 36 weeks’ postmenstrual age (PMA) were excluded. The growth rates from birth to 36 weeks’ PMA and follow-up outcomes at 18–22 months’ corrected age of EPT infants randomized at birth to either early CPAP (intervention group) or early intubation for surfactant administration (control group) were analyzed. RESULTS: 810 of 1316 infants enrolled in SUPPORT (414 in intervention group, 396 in control group) had growth data analyzed. Median gestational age was 26 weeks and mean birthweight was 839 grams. Baseline characteristics, total nutritional intake, and in-hospital comorbidities were not significantly different between groups. In a regression model, growth rates between birth and 36 weeks’ PMA as well as growth rates during multiple intervals from birth to day 7, day 7 to14, day 14 to 21, day 21 to 28, day 28 to 32 weeks’ PMA, and 32 weeks’ PMA to 36 weeks’ PMA did not differ between treatment groups. Independent of treatment group, higher growth rates from day 21 to day 28 were associated with a lower risk of Bayley III cognitive score

Objective To investigate associations in toddlers born extremely preterm ( Study design Cohort analysis from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Surfactant Positive Airway Pressure and Pulse Oximetry Trial Neuroimaging and Neurodevelopmental Outcomes Study of infants born extremely preterm. Subjects underwent cranial ultrasonography and near-term magnetic resonance imaging (MRI). At 18-22 months of corrected age, the assessment included the Brief Infant Toddler Social Emotional Assessment (BITSEA) Problem and Competence Scale scores and the Bayley Scales of Infant Development, Third Edition (Bayley-III). The BITSEA Problem Scale assesses dysregulation; the Competence Scale assesses social-emotional competence. We examined associations of Problem and Competence scores and positive screen rates with cranial ultrasonography and near-term MRI. Mean BITSEA and Bayley-III scores were compared using ANOVA and positive screen rates with the χ2 test. We computed correlations between BITSEA and Bayley-III scores. Results Of the 397 children, positive BITSEA screens were found in 34% for the Problem score and 26% for the Competence score. Presence of lesions on near-term MRI that included cerebellar lesions were significantly associated with lower BITSEA Competence but not with Problem scores; Competence scores were inversely related to the presence/significance of lesions. Positive screens on Competence scores and on both Competence and Problem scores were significantly associated with Bayley-III cognitive and language scores Conclusions Social–emotional competence contributes to deficits in cognitive and language development. Presence of injury on near-term MRI that includes cerebellar lesions is associated with later social–emotional competence and may be a useful predictor to guide early assessment and intervention. Trial registration ClinicalTrials.gov : NCT00063063 and NCT00233324 .

Objectives To identify variables associated with successful elective extubation, and to determine neonatal morbidities associated with extubation failure in extremely preterm neonates. Study design This study was a secondary analysis of the National Institute of Child Health and Human Development Neonatal Research Network's Surfactant, Positive Pressure, and Oxygenation Randomized Trial that included extremely preterm infants born at 240/7 to 276/7 weeks' gestation. Patients were randomized either to a permissive ventilatory strategy (continuous positive airway pressure group) or intubation followed by early surfactant (surfactant group). There were prespecified intubation and extubation criteria. Extubation failure was defined as reintubation within 5 days of extubation. Results Of 1316 infants in the trial, 1071 were eligible; 926 infants had data available on extubation status; 538 were successful and 388 failed extubation. The rate of successful extubation was 50% (188/374) in the continuous positive airway pressure group and 63% (350/552) in the surfactant group. Successful extubation was associated with higher 5-minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within the first 24 hours of age and prior to extubation, lower partial pressure of carbon dioxide prior to extubation, and non-small for gestational age status after adjustment for the randomization group assignment. Infants who failed extubation had higher adjusted rates of mortality (OR 2.89), bronchopulmonary dysplasia (OR 3.06), and death/ bronchopulmonary dysplasia (OR 3.27). Conclusions Higher 5-minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within first 24 hours of age, lower partial pressure of carbon dioxide and fraction of inspired oxygen prior to extubation, and nonsmall for gestational age status were associated with successful extubation. Failed extubation was associated with significantly higher likelihood of mortality and morbidities. Trial registration ClinicalTrials.gov : NCT00233324 .

Objective To characterize actual achieved patterns of oxygenation in infants born appropriate vs small for gestational age (SGA) randomized to a lower (85-89%) vs higher (91%-95%) oxygen saturation target in the Surfactant Positive Pressure and Oxygen Trial. To determine the association between achieved oxygen saturation levels and survival in infants born appropriate vs SGA enrolled in the Surfactant Positive Pressure and Oxygen Trial. Study design Median oxygen saturation and intermittent hypoxemia events ( 0/7 -27 6/7 weeks of gestation while receiving supplemental oxygen during the first 3 days of life. Results Lower target infants who were small for gestational age had the lowest oxygen saturation and highest incidence of intermittent hypoxemia during the first 3 days of life. The lowest quartile of oxygen saturation (≤92%) during the first 3 days of life was associated with lower 90-day survival for both infants born appropriate and SGA. An increased incidence of intermittent hypoxemia events during the first 3 days of life was associated with lower 90-day survival only in infants born SGA. Conclusion Lower achieved oxygen saturation during the first 3 days of life was associated with lower 90-day survival in extremely preterm infants. Infants born SGA had enhanced vulnerability to lower oxygen saturation targets as evidenced by lower achieved oxygen saturation and an association between increased intermittent hypoxemia events and lower survival. Trial registration ClinicalTrials.gov: NCT00233324.

OBJECTIVE: To identify rates of overweight (BMI ≥85(th) percentile) and obesity (BMI ≥95(th) percentile) at 6-7 years of age and associated risk factors among extremely preterm infants born at < 28 weeks of gestation. STUDY DESIGN: Anthropometrics, blood pressure, and active and sedentary activity levels were prospectively assessed. Three groups were compared, those with BMI≥85(th) percentile (overweight or obese for age, height and sex) and ≥95(th) percentile (obese) versus 85(th) percentile), central fat (waist circumference> 90(th) percentile), spent more time in sedentary activity (20.5 versus 18.2 versus 16.7 hours/week), and had either systolic and/or diastolic hypertension (24% versus 26% versus 14 %) respectively. Post discharge weight gain velocities from 36 weeks postmenstrual age (PMA) to 18 months, and 18 months to 6-7 years were independently associated with BMI ≥85(th) percentile whereas weight-gain velocity from 18 months to 6-7 years was associated with obesity. CONCLUSIONS: One in five former extremely preterm infants is overweight or obese and has central obesity at early school age. Post discharge weight gain velocities were associated with overweight and obesity. These findings suggest the obesity epidemic is spreading to the most extremely preterm infants. Trial registration ClinicalTrials.gov NCT00063063 and NCT0000

To test whether infants randomized to a lower oxygen saturation (peripheral capillary oxygen saturation [SpO2]) target range while on supplemental oxygen from birth will have better growth velocity from birth to 36 weeks postmenstrual age (PMA) and less growth failure at 36 weeks PMA and 18-22 months corrected age.We evaluated a subgroup of 810 preterm infants from the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, randomized at birth to lower (85%-89%, n = 402, PMA 26 ± 1 weeks, birth weight 839 ± 186 g) or higher (91%-95%, n = 408, PMA 26 ± 1 weeks, birth weight 840 ± 191 g) SpO2 target ranges. Anthropometric measures were obtained at birth, postnatal days 7, 14, 21, and 28; then at 32 and 36 weeks PMA; and 18-22 months corrected age. Growth velocities were estimated with the exponential method and analyzed with linear mixed models. Poor growth outcome, defined as weight10th percentile at 36 weeks PMA and 18-22 months corrected age, was compared across the 2 treatment groups by the use of robust Poisson regression.Growth outcomes including growth at 36 weeks PMA and 18-22 months corrected age, as well as growth velocity were similar in the lower and higher SpO2 target groups.Targeting different oxygen saturation ranges between 85% and 95% from birth did not impact growth velocity or reduce growth failure in preterm infants.

The purpose of the Minisymposium on Molecular Embryology and the Study of Lung Development was to identify promising approaches to understanding the molecular basis oflung morphogenesis in the embryo. The rationale for holding such a meeting was that by studying the molecular basis of lung morphogenesis, a great deal of fundamental information will be obtained about the molecular and genetic programs that influence processes not only oflung morphogenesis and maturation but also lung injury, lung repair, and lung carcinogenesis. The overall consensus of the Society for Developmental Biology meeting at which this Minisymposium was held was that "much is known about cells, but little is known about organ formation."

Complementary molecular and genetic approaches are yielding information about gain- versus loss-of-function phenotypes of specific genes and gene families in the embryonic, fetal, neonatal, and adult lungs. New insights are being derived from the conservation of function between genes regulating branching morphogenesis of the respiratory organs in Drosophila and in the mammalian lung. The function of specific morphogenetic genes in the lung are now placed in context with pattern-forming functions in other, better understood morphogenetic fields such as the limb bud. Initiation of lung morphogenesis from the floor of the primitive foregut requires coordinated transcriptional activation and repression involving hepatocyte nuclear factor-3β, Sonic hedgehog, patched, Gli2, and Gli3 as well as Nkx2.1. Subsequent inductive events require epithelial-mesenchymal interaction mediated by specific fibroblast growth factor ligand-receptor signaling as well as modulation by other peptide growth factors including epidermal growth factor, platelet-derived growth factor-A and transforming growth factor-β and by extracellular matrix components. A scientific rationale for developing new therapeutic approaches to urgent questions of human pulmonary health such as bronchopulmonary dysplasia is beginning to emerge from work in this field.

The objective of this workshop was to bring together in­ vestigators engaged in basic studies of organ development in order to facilitate discussion on epithelial-cell lineage in the lung. Although the bronchial epithelium and the alve­ olar epithelium contain transiently proliferating cells, it is not known whether there are any more pluripotent stem cells in these two compartments in the adult lung. It is also not known whether all alveolar type II cells and airway basal and secretory cells are capable of division, nor is it known what are the local restrictions or mechanisms of control of cell proliferation in vivo. Cell lineage is impor­ tant for the understanding of lung development, injury, re­ pair, and carcinogenesis. Since a great deal of progress has been made in identi­ fying stem cells in other organ systems, such as neural crest, intestine, liver, pancreas, testes, and the ocular lens, it was hoped that a multidisciplinary discussion of the concepts of epithelial stem-cell biology and a review of the data in these other organ systems might suggest ap­ proaches applicable to the study of pulmonary stem-cell biology.

Objective. —To develop a consensus on the use of antenatal corticosteroids for fetal maturation in preterm infants. Participants. —A nonfederal, nonadvocate, 16-member consensus panel including representatives from neonatology, obstetrics, family medicine, behavioral medicine, psychology, biostatistics, and the public; 19 experts in neonatology, obstetrics, and pharmacology presented data to the consensus panel and a conference audience of approximately 500. Evidence. —An extensive bibliography of references was produced for the consensus panel and the conference audience using a variety of on-line databases including MEDLINE. The consensus panel met several times prior to the conference to review the literature. It also commissioned an updated meta-analysis, a neonatal registry review, and an economic analysis that were presented at the conference. The experts prepared abstracts for distribution at the conference, presented data, and answered questions from the panel and audience. The panel evaluated the strength of the scientific evidence using the grading system developed by the Canadian Task Force on the Periodic Health Examination and adapted by the US Preventive Services Task Force. Consensus. —The consensus panel, answering predefined consensus questions, developed their conclusions based on the scientific evidence presented in open forum and the scientific literature. Consensus Statement. —The consensus panel composed a draft statement that was read in its entirety at the conference for comment. The panel released a revised statement at the end of the conference and finalized the revisions a few weeks after the conference. Conclusions. —Antenatal corticosteroid therapy is indicated for women at risk of premature delivery with few exceptions and will result in a substantial decrease in neonatal morbidity and mortality, as well as substantial savings in health care costs. The use of antenatal corticosteroids for fetal maturation is a rare example of a technology that yields substantial cost savings in addition to improving health. (JAMA. 1995;273:413-418)

The pathway for histidinle biosyinthesis in Salmonella typhimurium, elucidated largely through the efforts o:f Dr. B. N. Ames and co-workers, 1-5 is shown in Figure 1. The figure also shows that portioin of the pathway for puriine biosynthesis which involves the further metabolism of 4-amino-5-imidazole carboxamide riboinucleotide (phosphoribosyl-AIC).6 Dr. Phillip Hartmain and his colleagues have shown that the structural genes for the enzymes catalyziing the reactioins of the histidine pathway are localized in a small segment of the bacterial chromosome, the histidine operon.7' 8 The phenomenoni of coordiniate derepressioin of the histidine enzymes was originally described by Ames and Garry, 9 who found that the histidine operon functions as a single unit in response to the level of histidiine available to the organism. Evidence presented by Martin10 inidicates that the histidinie operon is transcribed into a polycistroiiic messenger-RNA, anid studies oIn polarity in the histidine operon7' 11,12 suggest that this messenger-RNA is trainslated from the end which

Kinetic studies on the derepression of 5 of the 10 enzymes for histidine biosynthesis in Salmonnella typhimurium reveal that derepression may proceed by two different modes, depending upon the site of mutation in the various histidine auxotrophs examined. Simultaneous derepression of the enzymes is observed in those mutants incapable of producing the intermediate, 4-amino-5-imidazolecarboxamide ribonucleotide, through the histidine pathway. Derepression of the enzymes in a temporal sequence corresponding to the positional sequence of the genes in the histidine operon is observed in those mutants which do produce this intermediate. The addition of 4-amino-5-imidazolecarboxamide ribonucleoside to cultures of mutants ordinarily characterized by the simultaneous mode of derepression served to shift the mode from simultaneous to sequential, but did not influence the derepressed rate of enzyme synthesis. In organisms in which the sequential mode is ordinarily observed, adenine effected a shift to the simultaneous mode, causing all the enzymes to derepress at the same time, but did not influence the derepressed rate of enzyme synthesis. Chloramphenicol, at low concentrations, reduced the growth rate of derepressed cells by a factor of 2 to 3 and decreased the rate of derepression of the histidine enzymes in all organisms tested. In the histidine auxotroph, hisE11, and in the wild type, LT-2 (derepressed by the addition of thiazole alanine), chloramphenicol prolonged the intervals between the times of derepression of the histidine enzymes. On the other hand, in hisG52, in which the enzymes for histidine biosynthesis derepress simultaneously and not sequentially, chloramphenicol did not alter the time of derepression of the enzymes. In the presence of chloramphenicol, adenine shifted the mode of derepression of hisE11 and LT-2 from sequential to simultaneous, just as it did in the absence of chloramphenicol. However, adenine did not eliminate the effect of chloramphenicol on the rate of depression. The data presented here suggest that the histidine operon is transcribed into a polycistronic message which, under conditions in which sequential derepression is observed, is translated from one end only. Under conditions in which simultaneous derepression is observed, the translation of this message is initiated at multiple sites.

Kinetic studies on repression of the enzymes for histidine biosynthesis in Salmonella typhimurium showed that, upon addition of histidine to a derepressed culture, the enzymes became repressed in a temporal sequence which corresponds with the positional sequence of the genes in the histidine operon. This serial pattern of repression occurred under conditions in which the feedback site of the first enzyme for histidine biosynthesis is intact. When this site was rendered nonfunctional the pattern of repression was changed so that all of the enzymes became repressed concomitantly. These results suggest that the first enzyme for histidine biosynthesis plays a hitherto unrecognized role in control of the histidine system.

It would appear from these studies that nitrogen control reflects the catabolic capacity of the cell and that utilizable nitrogen sources and some carbon sources are, to some extent, in competition for this capacity. The series of catabolic events initiated by addition of D-amino acids or by growth on aldol sugars, in the presence of ammonia nitrogen in the growth medium, provide an opportunity for study of the positive aspect of nitrogen control under conditions where negative control predominates. This approach may eventually clarify the apparent interactions between the modification cascade components, PII and UT/UR, with the nitrogen regulatory gene, glnG. The utilization of nutrients by E. coli seems less a matter of energy than of expeditious use of whatever is offered in the diet. A comparison of the rate of increase of GS on cultural downshift with the rate of increase following D-glutamate addition would suggest that control by nitrogen limitation is about eight times more effective than positive activation by D-glutamate in the presence of ammonia nitrogen. This observation is consistent with the finding of an additive effect for the D-amino acids which can function as positive activators in GS regulation. It has been demonstrated for the wild-type organism that the increase in GS level generated by a mixture of D-glutamate, D-lysine, D-threonine, and glycine approximates the increase in GS level observed during step-down of the culture from an ammonia-sufficient to an ammonia-limited condition. This observation further supports the physiologic relevance of the effect of D-amino acids in nitrogen control and suggests that the apparent derepression of GS observed upon exhaustion of the ammonia nitrogen supply represents a composite of positive activation generated as alternative catabolic functions assume a greater importance. As might be expected, addition of D-glutamate to cells at the point of ammonia exhaustion had no additional positive effect. Following a downshift from glucose-ammonia-glutamine to glucose-glutamine cultural conditions, only the level of GS increases during the initial 60-minute observation period. This finding suggests that glutamine catabolism may, like D-threonine, D-lysine, and glycine, bypass the positive activation of GDH and GAT controls. The likely possibility in that the increases observed for GAT and GDH depend on D-glutamate as specific inducer. There are several instances where D-amino acids function as inducers of L-amino acid dehydrogenases and where amino acid racemase activity is directly coupled to flavoprotein dehydrogenases.(ABSTRACT TRUNCATED AT 400 WORDS)

The techniques of double isotope labeling and specific hybridization have been used to determine the size of the mRNA transcribed from the histidine operon in Salmonella typhimurium under conditions of derepression. The results obtained by both techniques agree with the previous results of Martin3 which demonstrated that, in a constitutive mutant, the histidine mRNA is polycistronic. Previous studies revealed that derepression of the enzymes for histidine biosynthesis may proceed by either of two modes1,2. One mode is characterized by simultaneous derepression of all the enzymes, whereas the other mode is characterized by the derepression of the enzymes in a temporal sequence which corresponds with the positional sequence of genes in the histidine operon. Since the present studies show that the mRNA transcribed from the histidine operon is always polycistronic, regardless of the mode of derepression, we may rule out the possibility that the difference between the two modes reflects any difference in the size of the histidine mRNA. Rather, the difference must lie in the manner in which the polycistronic histidine mRNA is translated.

Previous workt with adeninie-requiring auxotrophic mutaiits of Salmonella typhimurium showed that a sequential blockade in the biosynthesis of adenylic acid was due to the genetic loss of the bifunctional enzyme, adenylosuccinase (adenylosuccinate-AMP lyase, EC 4.3.2.2). The phenotypic conisequence of this mutation was a specific growth requirement for adenine and the accumulation of the substrate of the first reaction, succinyl-AICAR. By transductioni techniques the structural gene for this enzyme was localized on the Salmonella chromosome in a region designated as the pur-B locus. Subsequently, in vivo complementation was demonstrated among all the available pur-B mutants although none of these mutants showed any independent adenylosuccinase activity under the usual conditions of assay. 2 A new class of pur-B mutants with a uniquely altered adenylosuccinase has recently been identified. Examination of crude extracts for adenylosuccinase activity showed that this class of pur-B mutants contained a specific activity which was approximately 1/5 the adenylosuccinase activity measured in extracts of the wild type. The growth pattern of the members of this group, as well as the variation of their adenylosuccinase activity with nutritional history, suggested an unusual repression effect. Comparisons between the wild-type and mutant adenylosuccinase revealed several differences in stability characteristics. Moreover, the failure to demonstrate any gene product, which was cross-reactive with the enzymeneutralizing antibody, in extracts prepared from mutant cells grown in excess adenine further suggested a repression concomitant with the mutant alteration. This communication will present the results of studies with Salmonella typhimurium, strain pur-91, a representative of the new class of pur-B mutants.